Over the past several years, the United States Food and Drug Administration (FDA) and the United Kingdom regulatory authority (CPMP) have recommended that all new drugs have electrocardiogram (ECG) testing to determine any effects of the new agent on humans, particularly the effects on the QTc interval of a patient's ECG. Several companies support these clinical trials by serving as centralized collection and interpretation points or laboratories for the handling, analysis and data reporting of these ECGs (hereinafter referred to as “processing companies”). Most processing companies rely on ECG machines programmed with algorithms for measuring the important ECG intervals (such as the heart rate, PR, QRS, QT and QTc durations), and a cardiologist later reviews the intervals and interprets the ECG's morphology. Reliance on ECG machines for determining interval duration leads to inconsistent and potentially less accurate results, intrinsically as well as between different machine programs. Further, ECG machines have difficulty identifying low frequency waves, leading to false positive and false negative readings, especially with respect to the QT intervals.
For several years, the assignee of the present application—eResearchTechnology, Inc. (eRT) of Philadelphia, Pa.—has been in the business of supporting clinical drug trials by providing centralized collection and interpretation of ECG services. The assignee, however, does not rely upon ECG machine measurements in measuring ECG intervals, but instead uses manual measurement techniques. This practice, although very accurate and reliable, further complicates the already cumbersome and paper-intensive process of generating regulatory-grade research data from ECG tracings for a sponsor of a clinical trial (i.e., data that are supported by an audit trail and are 100% verifiable by a government agency such as the FDA). An overview of this process is provided hereafter.
A sponsor, such as a pharmaceutical company, conducts clinical trials that typically include patients throughout the world. Each patient in a trial normally undergoes a series of ECG tests conducted during a series of visits to a study site (e.g., a doctor's office or hospital). The visits generally must occur during time periods specified by the sponsor in the research protocol. At several of these visits, an ECG machine is used to perform an ECG test and an ECG tracing is produced. The site collects ECG tracings from several patients in the clinical trial and forwards the ECG tracings to eRT, along with demographic data associated with each ECG. The demographic data usually include information such as a patient identifier, a study site identifier, the date of the test, the time of the test, a clinical trial identifier, the drug being tested, and the visit number for the patient (e.g., baseline, first visit, second visit, etc.). The demographic data are generally recorded on a label attached to the ECG reading. Alternatively, the demographic data and the ECG tracing are sent to eRT via electronic communications through a telephone network. In this alternative, the tracing and demographic data are then printed by eRT for later processing.
Once an ECG tracing is received, a source processing department manually enters the demographic information into a computer database via a computer and through a standard data entry screen. The screen is generic for all trials handled by eRT and, therefore, often includes data entry windows or areas that are extraneous and not pertinent to a particular trial. After the data are saved to a database, it must be confirmed that there have been no data entry mistakes. If a mistake is noted on the demographic information on the label, for example the patient's age was entered incorrectly on the label, or if a piece of demographic information is missing from the label, then a regulatory grade query must be conducted and documented. A query is forwarded to the query resolution department in the form of a paper copy of the ECG along with a note indicating the required query. A member of the query resolution department then telephones a study site or a site investigator associated with the study site to try to resolve any discrepancy or obtain any missing information from the demographic data. Telephone logs are maintained, and corrections are made directly onto the source document (the combined ECG and demographic label), initialed and dated. While the query resolution team conducts queries, the source document must be kept within the interpretation process so that the process can continue in parallel with the query resolution process; hence, copies of the source document are provided to the query resolution team.
A file associated with the ECG tracing is then forwarded to a diagnostic specialist. The diagnostic specialist verifies the analysis requirements of the clinical trial from a protocol book. The protocol book includes the analysis requirements and any updates to these requirements for each clinical trial supported by eRT. Analysis requirements typically include information identifying how many heartbeats must be measured for QT intervals per individual ECG tracing and permissible time periods when patient visits may occur.
The diagnostic specialist typically identifies the heartbeats that are to be measured with pen marks placed on each individual ECG tracing. The ECG tracing is then mounted on a magnetic board, and intervals are measured. A pointer device is placed on top of the ECG tracing. A first edge of an interval is visually identified using the assistance of a magnifying glass, and the pointer device is aligned over the first edge. A button is then depressed on the device, and a data point is registered with a dedicated, stand-alone computer connected to the pointer device. A second edge of the interval being measured is then identified in a like manner, and a second data point is registered. This process is typically repeated for PR, QRS, RR, QTc and QT intervals in order to compile separate interval duration measurements (IDMs) associated with at least three heartbeats. The interval data are then saved to the stand-alone computer, and the interval data are then transferred to a central computer server. A work sheet identifying a calculated mean of the measurement data for each interval is then printed and attached to the ECG tracing in its file. The diagnostic specialist then sorts worksheets and ECG tracings for the assigned cardiologist's review. If an ECG tracing is somehow separated from its file, the ECG tracing and worksheet are placed in a “return to file” bin. Any ECG tracings and worksheets in the “return to file” bin are then matched with the appropriate file by a member of the source processing team.
Once an ECG and its associated worksheet are placed in the correct file, the diagnostic specialist forwards the file to the assigned cardiologist for review. The cardiologist reviews the ECG and completes the worksheet. The cardiologist indicates his or her medical interpretation of the measured intervals and the ECG morphology on the worksheet. Some studies require the cardiologists to also review ECG tracings from prior patient visits and a baseline visit along with the current ECG tracing being evaluated. Satisfying this preference requires the physical retrieval of files from a filing system and the concomitant local storage of hardcopy files throughout the duration of a clinical trial.
Some of the ECG tracings are then forwarded to the quality control department based upon predetermined quality control criteria. For example, every ECG tracing associated with a worksheet that indicates that an abnormal interval is present is sent to quality control for review. These files are identified for the quality control department with POST-IT notes, produced by 3M Corp., affixed to each file. Also, 5% of all other ECG tracings are pulled for quality control. Additionally, a member of the quality control team telephones a sponsor, or a member of the source processing team faxes a sponsor, when certain criteria are met, e.g., a measured QT interval for an individual ECG tracing falls within a predefined dangerous range. After an ECG has been quality controlled or passed over for quality control, a member of the source processing group faxes a preliminary reporting of the cardiologist's evaluation to the study site and/or the sponsor, as dictated by the trial protocol. The source processing department then sorts the worksheets and ECG tracings for data entry. The cardiologist's comments and analysis from each worksheet are entered into a database by a source processing member. Source processing then prints a final report and clips it to the worksheet and ECG tracing. The query resolution department then quality controls the data entry on the final report. Next, source processing photocopies the final report for the site and the sponsor. The final report is then sent to the site or sponsor by Federal Express or other courier according to the protocol for the clinical trial. This reporting is typically accomplished approximately ten days after the initial facsimile reporting. Source processing then files the patient's file on-site. All of the files associated with a clinical trial are archived at the end of a clinical trial.
It should be apparent from the above description that the current collection, interpretation and reporting process is very paper and task intensive. While the process ultimately produces regulatory-grade research data, there remains a need for an improved method and system that increases the efficiency and flexibility of the collection, interpretation and reporting process while generating regulatory-grade research data that is supported by an audit trail.